Design, synthesis and biological evaluation of indoline-maleimide conjugates as potential antitumor agents for the treatment of colorectal cancer.

An efficient protocol for direct coupling of maleimides and indolines at the C7-position was achieved under Rh(III) catalysis. Thirty four novel indoline-maleimide conjugates were prepared in good to excellent yields using this method. All compounds were evaluated for their anti-proliferative effect against colorectal cell lines. Among them, compound 3ab showed the most potent anti-proliferative activity against the CRC cells, and displayed low toxicity in the normal cell. Further investigation indicated that 3ab could effectively suppress the proliferation and migration of CRC cells, along with inducing cell cycle arrest and apoptosis. Mechanistic studies revealed that compound 3ab inhibited the proliferation of CRC cells via suppressing the AKT/GSK-3ß pathway. In vivo evaluation demonstrated remarkable antitumor effect of 3ab (10 mg/kg) in the HCT116 xenograft model with no obvious toxicity, which is superior to that of 5-Fluorouracil (20 mg/kg). Therefore, conjugate 3ab could be considered as a potential CRC therapy agent for further development.

Removal of Cr(VI) from aqueous solution using ball mill modified biochar: multivariate modeling, optimization and experimental study.

Chromium (Cr(VI)) pollution has attracted wide attention due to its high toxicity and carcinogenicity. Modified biochar has been widely used in the removal of Cr(VI) in water as an efficient and green adsorbent. However, the existing biochar prepared by chemical modification is usually complicated in process, high in cost, and has secondary pollution, which limits its application. It is urgent to explore modified biochar with simple process, low cost and environmental friendliness. Therefore, ball milling wheat straw biochar (BM-WB) was prepared by ball milling technology in this paper. The adsorption characteristics and mechanism of Cr(VI) removal by BM-WB were analyzed by functional group characterization, adsorption model and response surface method. The results showed that ball milling effectively reduced the particle size of biochar, increased the specific surface area, and more importantly, enhanced the content of oxygen-containing functional groups on the surface of biochar. After ball milling, the adsorption capacity of Cr(VI) increased by 3.5-9.1 times, and the adsorption capacity reached 52.21 mg/g. The adsorption behavior of Cr(VI) follows the pseudo-second-order kinetics and Langmuir isotherm adsorption model rate. Moreover, the Cr(VI) adsorption process of BM-WB is endothermic and spontaneous. Under the optimized conditions of pH 2, temperature 45 °C, and adsorbent dosage 0.1 g, the removal rate of Cr(VI) in the solution can reach 100%. The mechanism of Cr(VI) adsorption by BM-WB is mainly based on electrostatic attraction, redox and complexation. Therefore, ball milled biochar is a cheap, simple and efficient Cr(VI) removal material, which has a good application prospect in the field of remediation of Cr(VI) pollution in water.

Sustainable development of environmental protection talents training: Research on the behavior decision of government, university and enterprise under the background of evolutionary game.

Environmental protection talents training (EPTT) is recognized as a key prerequisite for maintaining environmental sustainability, and in order to study the influence of each player on EPTT. This paper innovatively constructs a tripartite evolutionary game model of government, university and enterprise. The equilibrium points and evolutionary stabilization strategies of each participant are solved by replicating the dynamic equations, and the behaviors of each subject in EPTT are analyzed so as to clarify the behavioral characteristics and optimal strategies of the government's participation in EPTT. The results show that enterprises occupy a more important position in influencing government decisions. The government should reduce the financial incentives for enterprises and replace them with greater policy support. Meanwhile, the government should actively promote the cultivation mechanism that integrates universities and enterprises. The results of the study can provide a decision-making basis for the government to promote the sustainable development of EPTT.

Integrated multi-omics reveal gut microbiota-mediated bile acid metabolism alteration regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease.

Gut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn's disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn's disease, and the response to anti-α4ß7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn's disease initiating anti-α4ß7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4ß7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4ß7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.

Expression and effect of miR­27b in primary liver cancer.

The occurrence and development of primary liver cancer is associated with microRNA. Specifically, the expression of microRNA-27b (miR-27b) is upregulated in four liver cancer drug-resistance cell lines. Despite that, the function of miR-27b in liver cancer is not clear yet. The aim of the present study was to investigate the effect of miR-27b expression during oncogenesis, cell proliferation, apoptosis and chemotherapy resistance development in a model of liver cancer. Expression of miR-27b was detected with reverse transcription-quantitative PCR. To establish stable overexpression of miR-27b and negative control liver cancer cell lines, a lentiviral pre-miR-27b overexpression vector and negative control vector were transfected into each cell line. Cell Counting Kit-8 assay, clone formation assay and immunohistochemical assay were used to detect cell proliferation. Apoptosis and drug sensitivity were detected by flow cytometry and MTT assay, respectively. The expression level of miR-27b in liver cancer tissues was also lower than in liver tissues adjacent to the tumor. Two stable miR-27b overexpression liver cancer cell lines (Huh-7/miR-27b and HepG2/miR-27b) and their control cell lines (Huh-7/NC and HepG2/NC) were successfully constructed. It was revealed that upregulation of miR-27b can suppress cell proliferation, promote cell apoptosis and chemotherapy resistance. In addition, the findings of the present study demonstrated that patients with cirrhosis expressed lower miR-27b compared with patients without cirrhosis. The expression level of miR-27b was significantly associated with the age, serum alpha-fetoprotein and alanine aminotransferase level of patients with liver cancer. Meanwhile, it was indicated that the disease survival time of the low miR-27b expression group was longer than that of the high miR-27b expression group. The present study suggested that miR-27b functions as a liver cancer suppressor. Moreover, miR-27b can act as a biomarker to estimate drug sensitivity to chemotherapy in patients with liver cancer.

The Recent Advances of Polymer-POSS Nanocomposites With Low Dielectric Constant.

This study provides a comprehensive overview of the preparation methods for polyhedral oligomeric silsesquioxane (POSS) monomers and polymer/POSS nanocomposites. It focuses on the latest advancements in using POSS to design polymer nanocomposites with reduced dielectric constants. The study emphasizes exploring the potential of POSS, either alone or in combination with other materials, to decrease the dielectric constant and dielectric loss of various polymers, including polyimides, bismaleimide resins, poly(aryl ether)s, polybenzoxazines, benzocyclobutene resins, polyolefins, cyanate ester resins, and epoxy resins. In addition, the research investigates the impact of incorporating POSS on improving the thermal properties, mechanical properties, surface properties, and other aspects of these polymers. The entire study is divided into two parts, discussing systematically the role of POSS in reducing dielectric constants during the preparation of POSS composites using both physical blending and chemical synthesis methods. The goal of this research is to provide valuable strategies for designing a new generation of low dielectric constant materials suitable for large-scale integrated circuits in the semiconductor materials domain.

On the adsorption characteristics and mechanism of methylene blue by ball mill modified biochar.

In this study, modified biochar (BRB) was prepared from rice straw by ball milling technique and used for the adsorption of methylene blue (MB) in wastewater. The BRB was characterized by SEM, FTIR and XPS, and the adsorption model and Box-Behnken design were used to optimize the five influencing factors. The results showed that the ball milling technique could increase the content of functional groups (-OH, C=C and C-O, etc.) and aromatic structures on the surface of biochar, thus facilitating the removal of MB. The isotherm model was consistent with the Langmuir adsorption model (R2 = 0.947) and the maximum adsorption capacity was 50.27 mg/g. The adsorption kinetics was consistent with the pseudo-second-order kinetic model (R2 = 1) and the adsorption rate was mainly controlled by chemisorption. The thermodynamic model confirmed that the adsorption process was a spontaneous heat absorption reaction. The maximum adsorption efficiency was 99.78% under the optimal conditions (40℃, pH 8, reaction time = 90 min, dosing amount = 0.1 mg), and the adsorption efficiency could be improved by increasing the pH and BRB dosing amount. The surface functional groups and crystal structure properties of BRB were the main determinants of adsorption, and it was clarified that physical adsorption, electrostatic attraction and π-π interaction were the main mechanisms for the adsorption of MB by BRB. The main mechanisms were clarified. Therefore, BRB is an economic, efficient and green adsorption material with good potential for the removal of dye pollutants in the aqueous environment.

Progress in organic photovoltaics based on green solvents: from solubility enhancement to morphology optimization.

Solution-processed organic photovoltaics (OPVs) is one of the most promising photovoltaic technologies in the energy field, due to their clean and renewable low-cost manufacturing potential. OPV has rapidly developed with the design and synthesis of highly efficient photovoltaic materials and the development of smart device engineering. To date, the majority of advanced OPV devices have been prepared using halogenated solvents, achieving power conversion efficiencies (PCE) exceeding 19% on a laboratory scale. However, for industrial-scale production, less toxic manufacturing processes and environmental sustainability are the key considerations. Therefore, this review summarizes recent advances in green solvent-based approaches for the preparation of OPVs, highlighting material design (including polymer donors and small molecule acceptors) and device engineering (co-solvent methods, additive strategies, post-treatment methods, and regulation of coating method), emphasizing crucial factors for achieving high performance in green solvent-processed OPV devices. This review presents potential future directions for green solvent-based OPVs, which may pave the way for future industrial development.

Heterologous Expression and Characterization of a Thermostable α-L-Rhamnosidase from Thermoclostridium stercorarium subsp. thermolacticum DSM 2910 and Its Application in the Biotransformation of Rutin.

An α-L-rhamnosidase gene from Thermoclostridium. stercorarium subsp. thermolacticum DSM 2910 (TstRhaA) was cloned and expressed. The maximum TstRhaA activity of the protein reached 25.2 U/ml, and the molecular mass was approximately 106.6 kDa. The protein was purified 8.0-fold by Ni-TED affinity with an overall recovery of 16.6% and a specific activity of 187.9 U/mg. TstRhaA activity was the highest at 65°C and pH 6.5. In addition, it exhibited excellent thermal stability, better pH stability, good tolerance to low concentrations of organic reagents, and high catalytic activity for p-nitrophenyl-α-L-rhamnopyranoside (pNPR). Substrate specificity studies showed that TstRhaA exhibited a high specific activity for rutin. At 60°C, pH 6.5, and 0.3 U/ml enzyme dosage, 60 g/l rutin was converted to 45.55 g/l isoquercitrin within 150 min. The molar conversion rate of rutin and the yield of isoquercitrin were 99.8% and 12.22 g/l/h, respectively. The results suggested that TstRhaA could be used for mass production of isoquercitrin.

Gut microbiota-related bile acid metabolism-FXR/TGR5 axis impacts the response to anti-α4ß7-integrin therapy in humanized mice with colitis.

The gut microbiota and bile acid metabolism are key determinants of the response of inflammatory bowel disease to biologic therapy. However, the molecular mechanisms underlying the interactions between the response to anti-α4ß7-integrin therapy and the gut microbiota and bile acid metabolism remain unknown. In this research, we investigated the role of gut microbiota-related bile acid metabolism on the response to anti-α4ß7-integrin therapy in a humanized immune system mouse model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid. We found that anti-α4ß7-integrin significantly mitigated intestinal inflammation, pathological symptoms, and gut barrier disruption in remission-achieving colitis mice. Whole-genome shotgun metagenomic sequencing demonstrated that employing baseline microbiome profiles to predict remission and the treatment response was a promising strategy. Antibiotic-mediated gut microbiota depletion and fecal microbiome transplantation revealed that the baseline gut microbiota contained common microbes with anti-inflammatory effects and reduced mucosal barrier damage, improving the treatment response. Targeted metabolomics analysis illustrated that bile acids associated with microbial diversity were involved in colitis remission. Furthermore, the activation effects of the microbiome and bile acids on FXR and TGR5 were evaluated in colitis mice and Caco-2 cells. The findings revealed that the production of gastrointestinal bile acids, particularly CDCA and LCA, further directly promoted the stimulation of FXR and TGR5, significantly improving gut barrier function and suppressing the inflammatory process. Taken together, gut microbiota-related bile acid metabolism-FXR/TGR5 axis may be a potential mechanism for impacting the response to anti-α4ß7-integrin in experimental colitis. Thus, our research provides novel insights into the treatment response in inflammatory bowel disease.

Comparative efficacy and safety of combination therapy with infliximab for Crohn's disease: a systematic review and network meta-analysis.

PURPOSE: There is not enough information to position medications for the treatment of Crohn's disease (CD). Therefore, using a network meta-analysis and systematic review, we evaluated the efficacy and safety of combination therapy and infliximab (IFX) monotherapy in CD patients. METHODS: We identified randomized controlled trials (RCTs) in CD patients who were given IFX-containing combination therapy versus IFX monotherapy. Induction and maintenance of clinical remission were the efficacy outcomes, while adverse events were the safety outcomes. The surface under cumulative ranking (SUCRA) probabilities was used to assess ranking in the network meta-analysis. RESULTS: In total, 15 RCTs with 1586 CD patients were included in this study. There was no statistical difference between different combination therapies in induction and maintenance of remission. In terms of inducing clinical remission, IFX + EN (SUCRA: 0.91) ranked highest; in terms of maintaining clinical remission, IFX + AZA (SUCRA: 0.85) ranked highest. There was no treatment that was significantly safer than the others. In terms of any adverse events, serious adverse events, serious infections, and infusion/injection-site reactions, IFX + AZA (SUCRA: 0.36, 0.12, 0.19, and 0.24) was ranked lowest for all risks; while IFX + MTX (SUCRA: 0.34, 0.06, 0.13, 0.08, 0.34, and 0.08) was rated lowest for risk of abdominal pain, arthralgia, headache, nausea, pyrexia, and upper respiratory tract infection. CONCLUSION: Indirect comparisons suggested that efficacy and safety of different combination treatments are comparable in CD patients. For maintenance therapies, IFX + AZA was ranked highest for clinical remission and lowest for adverse events. Further head-to-head trials are required.

Multiphase Morphology with Enhanced Carrier Lifetime via Quaternary Strategy Enables High-Efficiency, Thick-Film, and Large-Area Organic Photovoltaics.

With the continuous breakthrough of the efficiency of organic photovoltaics (OPVs), their practical applications are on the agenda. However, the thickness tolerance and upscaling in recently reported high-efficiency devices remains challenging. In this work, the multiphase morphology and desired carrier behaviors are realized by utilizing a quaternary strategy. Notably, the exciton separation, carrier mobility, and carrier lifetime are enhanced significantly, the carrier recombination and the energy loss (Eloss ) are reduced, thus beneficial for a higher short-circuit density (JSC ), fill factor (FF), and open-circuit voltage (VOC ) of the quaternary system. Moreover, the intermixing-phase size is optimized, which is favorable for constructing the thick-film and large-area devices. Finally, the device with a 110 nm-thick active layer shows an outstanding power conversion efficiency (PCE) of 19.32% (certified 19.35%). Furthermore, the large-area (1.05 and 72.25 cm2 ) devices with 110 nm thickness present PCEs of 18.25% and 12.20%, and the device with a 305 nm-thick film (0.0473 cm2 ) delivers a PCE of 17.55%, which are among the highest values reported. The work demonstrates the potential of the quaternary strategy for large-area and thick-film OPVs and promotes the practical application of OPVs in the future.

Achieving and Understanding of Highly Efficient Ternary Organic Photovoltaics: From Morphology and Energy Loss to Working Mechanism.

Ternary strategy, adding an additional donor (D) or acceptor (A) into conventional binary D:A blend, has shown great potential in improving photovoltaic performances of organic photovoltaics (OPVs) for practical applications. Herein, this review is presented on how efficient ternary OPVs are realized from the aspects of morphology, energy loss, and working mechanism. As to morphology, the role of third component on the formation of preferred alloy-like-phase and vertical-phase, which are driven by the miscibility tuning, is discussed. For energy loss, the effect of the third component on the luminescence enhancement and energetic disordering suppression, which lead to favorable increase of voltage, is presented. Regarding working mechanism, dilution effect and relationships between two acceptors or donor/acceptor, which explain the observed device parameters variations, are analyzed. Finally, some future directions concerning ternary OPVs are pointed out. Therefore, this review can provide a comprehensive understanding of working principles and effective routes for high-efficiency ternary systems, advancing the commercialization of OPVs.

Design, synthesis and biological evaluation of novel chromone-maleimide hybrids as potent anti-inflammatory agents against LPS-induced acute lung injury.

Acute lung injury (ALI) is an acute inflammatory disease, which severely impacts lung function with a high lethality rate. Chromone and maleimide are very important moieties of anti-inflammatory agents. Here, forty new chromone-maleimide hybrids were readily synthesized using a Heck-type coupling strategy in good yields and were screened for their anti-inflammatory activity. A majority of these hybrids showed high inhibitory potency against LPS-stimulated release of pro-inflammatory cytokines in macrophages. Preliminary structure-activity relationship studies led to the discovery of highly potent inhibitors. Five of them were found to inhibit lipopolysaccharide (LPS)-induced IL-6 and TNF-α release in a dose-dependent manner with IC50 values in the nanomolar rang. Furthermore, in vivo administration of 5e and 5g resulted in distinctly attenuated LPS-induced ALI via inhibiting the inflammation. Thus it is evident from our study that these novel chromone-maleimide hybrids present promising therapeutic potential for ALI.

The Correlation Between MYO9B Gene Polymorphism and Inflammatory Bowel Disease in the Guangxi Zhuang Population.

OBJECTIVE: To analyze the correlation between site rs962917 of the MYO9B gene and inflammatory bowel disease (IBD) in the Guangxi Zhuang nationality population. METHODS: The intestinal mucosa tissue of 153 IBD subjects (Han and Zhuang patients only) in the Guangxi Zhuang autonomous region comprised the case group, and the intestinal mucosa tissue of 155 healthy subjects (Han and Zhuang patients only) in the same region represented the control group. Deoxyribonucleic acid was extracted from the intestinal mucosa tissue of each experimental group, and the MYO9B gene-target fragment containing the single nucleotide polymorphism (SNP) site rs962917 was designed. Finally, polymerase chain reaction products were obtained by amplification, analyzed, and compared using the sequencing results. RESULTS: The results indicated that the genotype frequency of the MYO9B SNP site rs962917 between Crohn's disease (CD) and control groups of Zhuang and Han participants differed significantly (P < 0.05). Furthermore, the genotype frequency of MYO9B site rs962917 differed significantly between the Zhuang and Han population groups (P < 0.05). CONCLUSION: Site rs962917 of the MYO9B gene is related to CD susceptibility and incidence among the Guangxi Zhuang population.

Tnfaip6 Secreted by Bone Marrow-Derived Mesenchymal Stem Cells Attenuates TNBS-Induced Colitis by Modulating Follicular Helper T Cells and Follicular Regulatory T Cells Balance in Mice.

Objective: To investigate the immunological mechanism of bone marrow-derived mesenchymal stem cells (BM-MSCs) in inflammatory bowel disease (IBD). Methods: Mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were intraperitoneally injected with phosphate-buffered saline, BM-MSCs, BM-MSCs with tumor necrosis factor-induced protein 6 (Tnfaip6) knockdown mediated by RNA interference recombinant adenovirus, and BM-MSCs-infected with control adenovirus or recombinant mouse Tnfaip6. The disease activity index, weight loss, and histological scores were recorded. Serum levels of Tnfaip6 and pro- and anti-inflammatory cytokines, including interleukin (IL)-21, tumor necrosis factor-alpha (TNF-α), IL-10 were measured by enzyme-linked immunosorbent assay. The relative expression levels of these cytokines, B-cell lymphoma 6 (BCL-6) and fork-like transcription factor p3 (Foxp3) in the colon were determined by real-time quantitative PCR (RT-qPCR). BCL-6 and Foxp3 are the master regulators of follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr), respectively. The infiltration of Tfh and Tfr in mesenteric lymph nodes (MLNs) and spleens was analyzed by flow cytometry. Results: Compared to the normal control group, the expression levels of BCL-6 and IL-21 in the colon, Tfh infiltration, and ratios of Tfh/Tfr in the MLNs and spleen, and the serum concentrations of IL-21 and TNF-α increased significantly in the colitis model group (p < 0.05). Intraperitoneal injection of BM-MSCs or Tnfaip6 ameliorated weight loss and clinical and histological severity of colitis, downregulated the expression of BCL-6, IL-21, and TNF-α, upregulated the expression of Foxp3, IL-10, and Tnfaip6 (p < 0.05), increased Tfr and reduced the infiltration of Tfh in the MLNs and spleen, and downregulated the Tfh/Tfr ratio (p < 0.05). On the other hand, BM-MSCs lost the therapeutic effect and immune regulatory functions on Tfh and Tfr after Tnfaip6 knockdown. Conclusion: Tfh increase in the inflamed colon, Tfh decrease and Tfr increase during the colitis remission phase, and the imbalance of the Tfh/Tfr ratio is closely related to the progression of IBD. Tnfaip6 secreted by BM-MSCs alleviates IBD by inhibiting Tfh differentiation, promoting Tfr differentiation, and improving the imbalance of Tfh/Tfr in mice.

Pathogenesis of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a chronic progressive liver disease whose etiology and pathogenesis are not yet clear. It is currently believed that the occurrence of AIH is closely related to genetic susceptibility and immune abnormalities, and other factors such as environment, viral infection and drugs that may cause immune dysfunction. This article reviews the pathogenesis of AIH and describes the latest research results in the past 5 years.

Unveiling structure-performance relationships from multi-scales in non-fullerene organic photovoltaics.

Unveiling the correlations among molecular structures, morphological characteristics, macroscopic properties and device performances is crucial for developing better photovoltaic materials and achieving higher efficiencies. To achieve this goal, a comprehensive study is performed based on four state-of-the-art non-fullerene acceptors (NFAs), which allows to systematically examine the above-mentioned correlations from different scales. It's found that extending conjugation of NFA shows positive effects on charge separation promotion and non-radiative loss reduction, while asymmetric terminals can maximize benefits from both terminals. Another molecular optimization is from alkyl chain tuning. The shortened alkyl side chain results in strengthened terminal packing and decreased π-π distance, which contribute high carrier mobility and finally the high charge collection efficiency. With the most-acquired benefits from molecular structure and macroscopic factors, PM6:BTP-S9-based organic photovoltaics (OPVs) exhibit the optimal efficiency of 17.56% (certified: 17.4%) with a high fill factor of 78.44%, representing the best among asymmetric acceptor based OPVs. This work provides insight into the structure-performance relationships, and paves the way toward high-performance OPVs via molecular design.

Chromone Derivatives CM3a Potently Eradicate Staphylococcus aureus Biofilms by Inhibiting Cell Adherence.

INTRODUCTION: The ability of Staphylococcus aureus to form biofilms is associated with high mortality and treatment costs. Established biofilms cannot be eradicated by many conventional antibiotics due to the development of antibiotic tolerance by S. aureus. Here we report the synthesis and biological characterization of novel small-molecule compounds with antibiofilm activity. Chromone 5-maleimide substitution compounds (CM3a) showed favorable antibacterial activity against S. aureus. METHODS: CM3A with antibacterial activity was synthesized and screened. The minimum inhibitory concentration (MIC) of CM3a were determined by the broth microdilution method. Biofilm eradication assay and colony count methods were used to investigate the effect of CM3a on S. aureus biofilm disruption and killing. Changes in biofilm architecture when subjected to CM3a, were visualized using confocal laser scanning microscopy (CLSM). CCK-8 assay and survival rate of Galleria mellonella larvae were used to test the toxicity of CM3a. RESULTS: The minimum inhibitory concentration (MIC) of CM3a against S. aureus was about 26.4 µM. Biofilm staining and laser scanning confocal microscopy analysis showed that CM3a eradicated S. aureus biofilms by reducing the viability of the constituent bacterial cells. On the other hand, CM3a showed negligible toxicity against mouse alveolar epithelial cells and Galleria mellonella larvae. CONCLUSION: Chromone derivatives CM3a has therapeutic potential as a safe and effective compound for the treatment of S. aureus infection.

Antibiofilm Activity of Small-Molecule ZY-214-4 Against Staphylococcus aureus.

Staphylococcus aureus is the most important pathogenic bacteria in humans. As the resistance of S. aureus to existing antibiotics is increasing, there is an urgent need for new anti-infective drugs. S. aureus biofilms cause persistent infections and resist complete eradication with antibiotic therapy. The present study investigated the inhibitory effect of the novel small-molecule ZY-214-4 (C1 9H1 1BrNO4) on S. aureus biofilm formation. At a subinhibitory concentration (4 µg/ml), ZY-214-4 had no effect on the growth of S. aureus strains and also showed no cytotoxicity in human normal bronchial epithelial cells (Bease-2B). The results of a semi-quantitative biofilm test showed that ZY-214-4 prevented S. aureus biofilm formation, which was confirmed by scanning electron microscopy and confocal laser scanning microscopy. ZY-214-4 significantly suppressed the production of polysaccharide intercellular adhesion and prevented cell aggregation, and also inhibited the mRNA expression of icaA and other biofilm-related genes (eno, clfA/B, fnbB, fib, ebpS, psmα, and psmß) in clinical S. aureus isolates. Thus, at a subinhibitory concentration, ZY-214-4 inhibits biofilm formation by preventing cell aggregation, highlighting its clinical potential for preventing or treating S. aureus infections.